Pathological conditions of atopic dermatitis, which is a refractory skin disease, include a nonallergic mechanism and an allergic mechanism. The former mechanism is represented by skin barrier dysfunction, and the latter mechanism is caused by an immune disorder. However, these pathological conditions cannot be strictly divided, since genetic factors and environmental factors causing the conditions are intricately interwound. Atopic dermatitis is induced and/or aggravated not only by genetic factors, but also by nonallergic factors, such as dry skin, and further by an immune disorder.
Understanding of refractory skin diseases, such as atopic dermatitis, is recently expanding. The current understanding is that the allergic mechanism includes an excessive release of histamine and an excessive secretion of protease and other substances due to the abnormal activation of mast cells and antigen-presenting cells at the affected area. It also includes an accelerated secretion of Th2 cell based interleukins, that is, IL-4, IL-5 and IL-13. Histamine causes the characteristic itch at the skin disease area. In addition, the increase of IL-4, IL-5 and IL-13 prevents the development of filaggrin, which is a skin barrier related protein, and of LL37, β-defensin-2, and β-defensin-3 exhibiting anti-microorganism activities, so the skin becomes vulnerable to microbial infection. The nonallergic mechanism is known to include increases in NADPH-oxidase and COX-2 activations according to an increase in sphingosyl phosphorylcholin in the corneal layer of the affected area, which increase the reaction products, that is, reactive oxygen species (ROS) and PG (prostaglandin) E2. These products also significantly inhibit filaggrin synthesis.
Meanwhile, it is traditionally known that an egg shell membrane (ESM) has advantageous effects, such as reducing inflammation and accelerating epithelium formation, when it is stuck on the area affected by a burn, a cut, a laceration or other injuries. An expectation for utilizing ESM effects has led to the development of various external agents. Specifically, Patent Document 1 teaches cosmetics having soluble egg shell membranes and glycerophospholipid blended in them, and Patent Document 2 teaches cosmetics having soluble egg shell membranes and sphingolipid blended in them. These examples were developed as cosmetics having skin beautifying effects and moisturizing effects, based on synergistic effects of soluble egg shell membranes combined with other active ingredients. Further, the egg shell membrane hydrolysate applied externally or administered orally is known to accelerate collagen synthesis in the skin. Patent Document 3 teaches utilizing this effect in a drink containing a hydrolytic egg shell membrane as an active ingredient.
Meanwhile, the inventors of the present invention reported that the low molecular compounds (CCK) contained in extracts derived from seaweed belonging to the brown algae have effects of selectively inhibiting activation of COX-2 (Patent Document 4).
Tarajo holly (scientific name: Ilex latifolia) is a tall evergreen tree belonging to Aquifoliaceae Ilex, and its leaves have been brewed and drunk as health tea in China. Tarajo holly leaf extract has been used in foods for Type I allergy, such as pollinosis. This use is conventionally understood to be based on an antihistamic effect. However, recent studies revealed that the tarajo holly leaf extract contains fisetin as the main ingredient and inhibits IL-13 generation in vivo. Japanese knotweed (scientific name: Fallopia japonica) is a perennial plant belonging to Polygonaceae. Not only is its dried root (Polygonum cuspidatum root: kojoukon) brewed and used to treat constipation, urticaria and other diseases, but its young buds of early spring are used in food. The Japanese knotweed leaf extract contains a considerable amount of quercetin, and quercetin has allergy reduction and elimination effects based on antioxidation effects.